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Semin Thromb Hemost 2004; 30: 81-88
DOI: 10.1055/s-2004-823006
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Heparin to Pentasaccharide and Beyond: The End Is Not in Sight

Harry L. Messmore1  Jr , William H. Wehrmacher1 , Erwin Coyne1 , Jawed Fareed1
  • 1Loyola University Medical Center, Maywood, Illinois
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Publication History

Publication Date:
13 April 2004 (online)

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The 87-year history of heparin began in 1916 when a 26-year-old medical student named Jay McLean startled his mentor William Howell, Professor of Physiology at Johns Hopkins University, by proclaiming that he had discovered “antithrombin.” This discovery was so surprising to Howell because he had expected McLean to isolate thromboplastin, a clot-promoting substance from animal tissue. In 1928, Charles Best, M.D., in Toronto, Canada, organized a team of chemists, physiologists, and surgeons to focus on the development of heparin. This group determined which animal tissues were the best source, had performed purification and identification, and had determined pharmacologic properties in vitro. By 1935, they were ready for human trials. By 1941, the group reported a series of 700 patients treated with the glycosaminoglycan called heparin. Meanwhile a critical cofactor, antithrombin, had been discovered at the University of Iowa (Brinkhous, et al). Introduction of newer tests for laboratory monitoring enabled refinement of dosages during the 1960s and 1970s. Its use permitted the development of hemodialysis and cardiopulmonary bypass surgery, and the prophylaxis of deep vein thrombosis in surgical patients. The concept of low-molecular-weight heparin occurred to Dr. Choay and others in France in the late 1970s. During the 1980s and 1990s, the development of low-molecular-weight heparins evolved for both prophylaxis and therapy. The first synthetic product was called the pentasaccharide, named for the five critical sugar units in heparin that bind to antithrombin (1983). Since then, this drug has been studied extensively to prove its clinical efficacy and safety.

KEYWORDS

Heparin - antithrombin - history - low-molecular-weight heparin - pentasaccharide

REFERENCES

  • 1 Messmore H, Wehrmacher W, Jeske W. From Heparin to Pentasaccharide. Oral Presentation at the Annual Meeting of the International Union of Angiology New York, NY; March, 2002
    Google Scholar
  • 2 McLean J. The thromboplastic action of heparin.  Am J Physiol. 1916;  41 250-257
    PubMedGoogle Scholar
  • 3 Jaques L. Addendum: the discovery of heparin.  Semin Thromb Hemost. 1978;  4 350-353
    PubMedGoogle Scholar
  • 4 McLean J. The discovery of heparin.  Circulation. 1959;  19 75-78
    CrossrefPubMedGoogle Scholar
  • 5 Howell W H, Holt E. Two new factors in blood coagulation-heparin and pro-antithrombin.  Am J Physiol. 1918;  17 328-341
    PubMedGoogle Scholar
  • 6 Howell W H. Heparin an anticoagulant.  Am J Physiol. 1922-1923;  63 434-435
    PubMedGoogle Scholar
  • 7 Howell W H. The purification of heparin and its chemical and physiologic reactions.  Johns Hopkins Hosp Med J. 1928;  42 199-205
    PubMedGoogle Scholar
  • 8 Best C H. Preparation of heparin and its use in the first clinical cases.  Circulation. 1959;  19 79-86
    PubMedGoogle Scholar
  • 9 Lam C. The strange story of Jay McLean, the discoverer of heparin.  Henry Ford Hosp Med J. 1985;  33 18-23
    PubMedGoogle Scholar
  • 10 Bigelow H G. Mysterious Heparin. The Key to Open Heart Surgery. Toronto; McGaw-Hill Ryerson 1990
    Google Scholar
  • 11 Roden L. Highlights in the history of heparin. In: Lane D, Lindahl U Heparin. Chemical and Biological Properties, Clinical Applications. London; Edward Arnold 1989: 1-23
    Google Scholar
  • 12 Best C H. Heparin and thrombosis.  Harvey Lect. 1941;  36 66-70
    PubMedGoogle Scholar
  • 13 Charles A F, Scott D A. Preparation of heparin from beef lung.  Trans Roy Soc Canada. 1934;  28 , sect V.55
    PubMedGoogle Scholar
  • 14 Scott D A, Charles A F. Studies on heparin III. The purification of heparin.  J Biol Chem. 1933;  102 437-448
    PubMedGoogle Scholar
  • 15 Charles A F, Scott D A. Studies on heparin II. Heparin in various tissues.  J Biol Chem. 1933;  102 431-435
    PubMedGoogle Scholar
  • 16 Charles A F, Scott IV D A. Observations on the chemistry of heparin.  Biochem J. 1936;  30 1927-1933
    CrossrefPubMedGoogle Scholar
  • 17 Scott D, Charles A. Studies on heparin. I. The preparation of heparin.  J Biol Chem. 1933;  102 425-436
    PubMedGoogle Scholar
  • 18 Best C H. Heparin and vascular occlusion.  Can Med Assoc J. 1936;  35 621-622
    PubMedGoogle Scholar
  • 19 Jaques L R, Waters E T. The isolation of crystalline heparin from the blood of dogs in anaphylactic shock.  Am J Physiol. 1940;  129 389-390
    PubMedGoogle Scholar
  • 20 Jacques L. Heparinase.  J Biol Chem. 1940;  133 445-451
    PubMedGoogle Scholar
  • 21 Murray G, Delorme E, Thomas N. Development of an artificial kidney and clinical experiences.  Arch Surg. 1947;  55 505-522
    PubMedGoogle Scholar
  • 22 Murray G, Best C. Heparin and thrombosis.  JAMA. 1940;  110 118-119
    PubMedGoogle Scholar
  • 23 Jorpes S. The chemistry of heparin.  Biochem J. 1935;  29 1817-1830
    PubMedGoogle Scholar
  • 24 Jorpes S. Heparin: a mucopolysaccharide and an active antithrombotic drug.  Circulation. 1959;  19 87-96
    PubMedGoogle Scholar
  • 25 Holmgren H, Wilander O. Beitrag zur Kenntnis der Chemie und Funktion der Ehrlichsen Mastzellen.  Zeitschr mikroscopisch anatomische Forschung. 1937;  42 242-245
    PubMedGoogle Scholar
  • 26 Nader H B, Dietrich C P. Natural occurrence and possible biological role of heparin. In: Lane DA, Lindahl U Heparin. London; Edward Arnold 1989: 81-113
    Google Scholar
  • 27 Bauer G. Clinical experiences of a surgeon in the use of heparin.  Am J Cardiol. 1964;  14 29-35
    CrossrefPubMedGoogle Scholar
  • 28 Wright I. The use of heparin as an antithrombotic agent-a panel discussion. In: Bradshaw R, Wessler S Heparin. Structure, Function and Clinical Implications. New York; Plenum Press 1975: 389-409
    Google Scholar
  • 29 Lam C. The neutralization of heparin by protamine.  Surgery. 1948;  2 197-199
    PubMedGoogle Scholar
  • 30 Barrowcliffe T. Heparin assays and standardization. In: Lane DA, Lindahl U Heparin. London; Edward Arnold 1989: 393-415
    Google Scholar
  • 31 Hyers T, Agnelli G, Hull R et al.. Antithrombotic therapy for venous thromboembolic disease.  Chest. 2001;  110 176S-193S
    PubMedGoogle Scholar
  • 32 Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time.  N Engl J Med. 1972;  287 324-327
    CrossrefPubMedGoogle Scholar
  • 33 Anand S, Ginsberg J S, Kearon C et al.. The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin.  Arch Intern Med. 1996;  156 1677-1681
    CrossrefPubMedGoogle Scholar
  • 34 Yin E T, Wessler S, Butler J V. Plasma heparin: a unique, practical submicrogram-sensitive assay.  J Lab Clin Med. 1973;  81 298-310
    PubMedGoogle Scholar
  • 35 Yin E T. Appraisal of clot based and amidolytic anti-Xa methods for the monitoring of heparin and its derivatives.  Semin Thromb Hemost. 1985;  11 243-244
    PubMedGoogle Scholar
  • 36 Holmer E. A new single chromogenic substrate assay for heparin-like anti-FXa activity in plasma.  Thromb Haemost. 1985;  54 (abst 29)
    PubMedGoogle Scholar
  • 37 Brinkhous K, Smith H, Warner E, Seegers W. The inhibition of blood clotting. An unidentified substance that acts in conjunction with heparin to prevent prothrombin conversion.  Am J Physiol. 1939;  125 683-687
    PubMedGoogle Scholar
  • 38 Levine M N, Hirsch J, Gent M et al.. A randomized trial comparing partial thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin.  Arch Intern Med. 1994;  154 49-56
    CrossrefPubMedGoogle Scholar
  • 39 Young E, Prins H M, Levine M N et al.. Heparin binding to plasma proteins:an important mechanism for heparin resistance.  Thromb Haemost. 1992;  67 639-643
    PubMedGoogle Scholar
  • 40 Rosenberg R D, Lam L. Correlation between structure and function of heparin.  Proc Natl Acad Sci USA. 1979;  76 1218-1222
    PubMedGoogle Scholar
  • 41 Yin E T, Wessler S. Heparin accelerated inhibition of factor X by its natural plasma inhibitor.  Biochim Biophys Acta. 1970;  201 387-390
    PubMedGoogle Scholar
  • 42 Kakkar V V, Spindler J, Corrigan T et al.. Efficacy of low doses of heparin in preventing deep vein thrombosis after major surgery.  Lancet. 1972;  2 101-106
    PubMedGoogle Scholar
  • 43 Sagar S. Efficacy of low dose heparin in prevention of extensive deep vein thrombosis in patients undergoing total hip replacement.  Lancet. 1976;  1 1151-1156
    PubMedGoogle Scholar
  • 44 Wehrmacher W, Karlman R, Scanlon P, Messmore H. Anticoagulant therapy of thromboembolic disease during pregnancy.  Compr Ther. 1998;  24 289-294
    PubMedGoogle Scholar
  • 45 Messmore H. Heparin induced thrombocytopenia: historical review.  Clin Appl Thromb Hemost. 1999;  5(suppl 1) 82-86
    PubMedGoogle Scholar
  • 46 Warkentin T. History of heparin induced thrombocytopenia. In: Warkentin T, Greinacher A Heparin Induced Thrombocytopenia. New York; Marcel Dekker 2001: 1-18
    Google Scholar
  • 47 Warkentin T. Heparin induced thrombocytopenia. In: Kitchens C, Alving B, Kessler C Consultative Hemostasis and Thrombosis. Philadelphia, PA; Elsevier Science 2002: 355-372
    Google Scholar
  • 48 Lam H, Silbert J, Rosenberg R P. The separation of active and inactive forms of heparin.  Biochem Biophys Res Commun. 1976;  69 570-577
    CrossrefPubMedGoogle Scholar
  • 49 Anderson L O, Barrowcliffe T W, Holmer E, Johnson E A, Sims G EC. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix bound antithrombin and by gel filtration.  Thromb Res. 1976;  9 545-583
    PubMedGoogle Scholar
  • 50 Hook M, Bjork J, Hopwood J, Lindahl U. Anticoagulant activity of heparin species by affinity chromatography on immobilized antithrombin.  FEBS Lett. 1976;  66 90-93
    CrossrefPubMedGoogle Scholar
  • 51 Willaime P, Choay J. A heparin story: from serendipity to rationality. 10th Anniversary International Symposium on Advances in Anticoagulant, Antithrombotic and Thrombolytic Drugs (AATD), the IBC Meeting, Boston, MA, October 1999
    Google Scholar
  • 52 Seegers W H, Marciniak E. Inhibition of autoprothrombin C activity with plasma.  Nature. 1962;  193 1188-1190
    PubMedGoogle Scholar
  • 53 Barlow G. Molecular weight distribution determinations on heparin samples.  Thromb Res. 1983;  31 513-519
    CrossrefPubMedGoogle Scholar
  • 54 Graham D, Pomeroy A. Relative activities of heparin fractions obtained by gel chromatography.  Thromb Haemost. 1979;  42 1598-1603
    PubMedGoogle Scholar
  • 55 Aiach M, Michaud A, Balian J-L, Lefevore M, Woler M, Fourtillan J. A new low molecular weight heparin derivative.  Thromb Res. 1983;  31 611-621
    CrossrefPubMedGoogle Scholar
  • 56 Holmer E, Karachi K, Soderstrom G. The molecular weight dependence of the rate enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin.  Biochem J. 1981;  193 395-400
    PubMedGoogle Scholar
  • 57 Weitz J L. Low molecular weight heparins.  N Engl J Med. 1997;  337 688-698
    CrossrefPubMedGoogle Scholar
  • 58 Jordan R E, Oosta G, Gardner W T. The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin.  J Biol Chem. 1980;  255 10081-10090
    PubMedGoogle Scholar
  • 59 Carter C J, Kelton J, Hirsh J, Cerskua A, Santos A. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits.  Blood. 1982;  59 1239-1245
    PubMedGoogle Scholar
  • 60 Holmer E, Soderberg K. Inhibition of heparin oligosaccharides by protamine chloride.  Semin Thromb Hemost. 1985;  11 241-242
    PubMedGoogle Scholar
  • 61 Palm M, Mattsen C. Pharmacokinetics of heparin and low molecular weight heparin fragment (Fragmin) in rabbits with impaired renal and metabolic clearance.  Thromb Haemost. 1987;  58 932-935
    PubMedGoogle Scholar
  • 62 Racanelli A, Fareed J, Walenga J M. Biochemical and pharmacological studies on protamine interactions with heparin, its fractions and fragments.  Semin Thromb Hemost. 1985;  11 176-189
    PubMedGoogle Scholar
  • 63 Bratt G, Tornebohm L, Widlund L et al.. Low molecular weight heparin (Kabi 2165 Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers.  Thromb Res. 1986;  42 613-620
    CrossrefPubMedGoogle Scholar
  • 64 Warkentin T E, Levine M N, Hirsh J et al.. Heparin induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin.  N Engl J Med. 1995;  332 1330-1335
    CrossrefPubMedGoogle Scholar
  • 65 Kakkar V V, Djazeri B, Fok J, Fletcher M, Scully M F, Westwick J. Low molecular weight heparins prevention of postoperative deep vein thrombosis.  BMJ. 1982;  284 375-379
    PubMedGoogle Scholar
  • 66 Turpie A GG, Levine M, Hirsh J, Carter C, Jay M, Powers P J. A randomized controlled trial of low molecular weight heparin (enoxaparin) to prevent deep vein thrombosis in patients undergoing elective hip surgery.  N Engl J Med. 1986;  315 925-929
    PubMedGoogle Scholar
  • 67 LeClerc J, Geerts W, Desjardins L. Prevention of VTE after knee arthroplasty: A randomized double blind trial comparing enoxaparin with warfarin.  Ann Intern Med. 1996;  124 619-626
    PubMedGoogle Scholar
  • 68 Knudsen M M, Morabito D, Parement G, Shackleford S. Use of low molecular weight heparin in preventing thromboembolism in trauma patients.  J Trauma. 1996;  41 446-459
    PubMedGoogle Scholar
  • 69 Litin S, Heit J, Mees K. Use of low molecular weight heparin in the treatment of venous thromboembolic disease. Answers to frequently asked questions.  Mayo Clin Proc. 1998;  73 545-551
    PubMedGoogle Scholar
  • 70 Samama M M. Contemporary laboratory monitoring of low molecular weight heparins.  J Clin Lab Med. 1995;  15 119-123
    PubMedGoogle Scholar
  • 71 Rabah M, Premmereur J, Graham M et al.. Usefulness of intravenous enoxaparin for percutaneous coronary intervention or unstable angina pectoris.  Am J Cardiol. 1999;  84 1391-1395
    CrossrefPubMedGoogle Scholar
  • 72 Koza M, Messmore H, Wallock M, Walenga J, Pifarre R. Evaluation of a low molecular weight heparins with standard heparin for hemodialysis in dogs.  Blood. 1984;  64(suppl 1) 238a
    PubMedGoogle Scholar
  • 73 Ibbotson T, Goa K. Enoxaparin. An update of its clinical use in the management of acute coronary syndromes.  Drugs. 2002;  62 1407-1431
    PubMedGoogle Scholar
  • 74 Lee A YY, Levine M N, Baker R I et al.. Low molecular weight heparin versus coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.  N Engl J Med. 2003;  349 146-153
    CrossrefPubMedGoogle Scholar
  • 75 Zacharsky L R. Malignancy as a solid phase coagulopathy: implications for the etiology, pathogenesis and treatment of cancer.  Semin Thromb Hemost. 2003;  29 239-246
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Kwaan H C, Parmar S, Wang J. Pathogenesis of increased risk of thrombosis in cancer.  Semin Thromb Hemost. 2003;  29 283-288
    Article in Thieme ConnectPubMedGoogle Scholar
  • 77 Valentine K A, Hull R D, Pineo G F. Low molecular weight heparin therapy and mortality.  Semin Thromb Hemost. 1997;  23 173-178
    PubMedGoogle Scholar
  • 78 Bick R L. Cancer associated thrombosis.  N Engl J Med. 2003;  349 109-111
    CrossrefPubMedGoogle Scholar
  • 79 Lee A YY, Levine M N, Baker R et al.. Low molecular weight heparin versus coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.  N Engl J Med. 2003;  349 146-153
    CrossrefPubMedGoogle Scholar
  • 80 Messmore H, Jeske W, Wehrmacher W, Walenga J. Benefit risk assessment of treatment for heparin-induced thrombocytopenia.  Drug Saf. 2003;  26 625-641
    CrossrefPubMedGoogle Scholar
  • 81 Walenga J, Jeske W, Samama M, Frapaise F, Bick R L, Fareed J. Fondaparinux: A synthetic heparin pentasaccharide as a new antithrombotic agent.  Expert Opin Investig Drugs. 2002;  11 1-11
    CrossrefPubMedGoogle Scholar
  • 82 Keam S, Goa K. Fondaparinux sodium.  Drugs. 2002;  62 1673-1685
    PubMedGoogle Scholar
  • 83 Eriksson B I, Bauer K A, Lassen M R, Turpie A GG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery.  N Engl J Med. 2001;  345 1298-1304
    CrossrefPubMedGoogle Scholar
  • 84 Bauer K A, Eriksson B I, Lassen M R, Turpie A GG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery.  N Engl J Med. 2001;  345 1305-1310
    CrossrefPubMedGoogle Scholar

Harry L Messmore JrM.D. 

Cancer Center, Loyola University Medical Center

2160 S. First Avenue

Maywood, IL 60153

Email: hlmehd64@aol.com

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